Angus Brown, University of Nottingham, UK
On 22 November 1917, Andrew Huxley was born. On this year’s anniversary, we celebrate the life and work of the Nobel Prize winning physiologist. Angus Brown (University of Nottingham) takes us back to Huxley’s early fascination with mechanics as a young boy and the notable career path that followed in building specialist equipment to better understand nerves and muscles.
The name of Andrew Huxley will be forever linked to that of Alan Hodgkin for their Nobel Prize winning work in uncovering the permeability changes that produce the action potential. Although the work was carried out on squid axons its universal relevance was evident in its applicability to all excitable membranes. This work ushered in the era of membrane biophysics, convincingly demonstrating the advantages of adopting a multidisciplinary approach to experimental design, and emphasising that advances in experimental techniques hasten scientific advances.
Given the global recognition of this work one could justifiably consider it the peak of Huxley’s scientific career and the work of which he was most proud. However, Huxley reveals an alternate view in his autobiographical recollections, where he gives a brief summary of the action potential work but displays far more enthusiasm for his work on muscle. Why was this?
Mechanically minded and childhood experiments
Its origins may lie in feelings of ownership and Huxley’s interests as a child captivated by mechanics. Indeed, it was physiology as the “the mechanical engineering of living machines” that attracted Huxley to the subject, a family trait since his grandfather Thomas Huxley founded The Physiological Society and advocated for consideration of physiology as an independent subject, a view adopted by Cambridge University in 1870. Huxley was given a lathe as a child and used it to create objects for his research throughout his career; many readers of this article might have had similar experiences, mechanical inquisitiveness naturally leading to adventures with circuit strip boards and soldering irons, the training ground for would-be electrophysiologists.
Hodgkin could claim ownership of the action potential, having commenced work in 1934, with Huxley, a recent graduate, recruited to Plymouth in August 1939 to spend a few weeks recording the intracellular action potential. The outbreak of World War II in early September 1939 abruptly curtailed their work. Huxley was unavailable to resume work with Hodgkin in 1947 due to wedding commitments and was unceremoniously replaced by Bernard Katz. He later returned to Plymouth in the summers of 1948 and 1949 to complete the voltage clamp studies.
He spent only a few months conducting squid experiments. He did however devote considerable effort from 1946 to 1948 optimising computations of the action potential, and from 1949 to 1952 analysing the data required for action potential reconstruction. Huxley was dissatisfied with the squid work. In his recollections, he explains that this was due to their ignorance of a 1902 paper by Overton suggesting a key role for Na+ in excitation. Huxley refers to this as a ‘stupid mistake’ and laments omission of the Na+ theory from their original 1939 paper and a fuller 1945 article.
Exploring muscle contraction
Huxley’s prose comes alive in his autobiographical recollections when discussing his work on muscle, which occupied him from 1952 to the twilight of his research career in 1984. Immediately after the submission of the five classic action potential papers with Hodgkin in 1952, Huxley changed fields and devoted the rest of his scientific career to uncovering the mechanisms involved in skeletal muscle contraction, a more tangible concern than the ethereal action potential.
This move was precipitated by the feeling that the issue of the action potential permeability had been solved, while the genetic world opened up by Watson and Crick was in the future. However, the equipment they had used was not of sufficient sensitivity to record gating currents created by the movement of charged particles within the membrane. Huxley realised there existed a large body of work from the previous one hundred years in relation to muscle contraction. He studied all available literature keenly aware of the consequences of an incomplete background when tackling a new subject.
Under the microscope
Huxley appreciated that the existing studies were based mostly on light microscopy, a technique unable to clearly resolve how the muscle contracted. Imagine his satisfaction in building an interference microscope, which would be capable of viewing the light and dark bands present in muscle fibre. His tool allowed him to observe that movement occurred due to changes in tension in the muscle fibres, which would suggest an underlying mechanism. He published his momentous sliding filament theory in 1954, only two years after the classic Hodgkin Huxley papers, and continued this work on muscle contraction in Cambridge until 1960 then at University College London, where he refined the experiments to determine how the action potential spread within the muscle via the transverse tubules with calcium as an activating factor. In the 1980s he became the master of Trinity College, Cambridge and President of the Royal Society where his roles became more administrative.
What sort of man was Huxley? His fearsome academic reputation led John Nichols to claim that Huxley seemed aloof, austere, and even frightening, whereas Alan McComas simply states that Huxley was the most brilliant man he ever met. Perhaps the last word should go to J Walter Woodbury, the man who nominated Hodgkin and Huxley for the Nobel Prize. He recollects meeting Huxley in 1961 and described a calculus problem in relation to his ongoing experimental studies on impulse conduction in the atrium that he was working on with my former boss, the greatly missed Wayne Crill. Huxley quietly handed him the solution the following morning.
The intricate machinery of the human body has been studied for centuries and yet there remain many mysteries to unfold. Throughout history to the present day, physiologists are dedicated to studying the science of life. This week, we celebrate these advances with Physiology Week. Check out our social media channels to see the amazing world of physiology and the current work of physiologists.